The aging process can be naturally accelerated and decelerated during evolution leading to significant diversity in lifespan among related species. Rodents represent a particularly convenient system to examine this diversity at the molecular level, because these animals are characterized by a ten-fold difference in lifespan and their tissues and cultured cells are readily available. Unbiased characterization of genes and processes that are associated with natural changes in lifespan within rodents may lead to the development of approaches that target the aging process and possibly delay it. We hypothesize that the lifespan of rodents is adjusted through a combination of order-wide and lineage-specific processes and provide preliminary data in support of this possibility. Project 4 will carry out gene expression and ribosome profiling analyses across rodent tissues and fibroblasts to identify and characterize these processes, focusing on DNA repair and metabolic processes known to regulate lifespan or occur in long-lived rodents. This project will further directly examine the functions of several unique protein forms we identified by sequencing the genome and transcriptome of the longest-lived rodent, the naked mole rat. Project 4 will test if these forms result in reduced mutagenesis in mouse cells and test the hypothesis that the naked mole rat telomeres have a high capacity to protect chromosome ends from genome instability. Finally, we will uncover and analyze gene expression and protein synthesis programs that are coordinately regulated in order to adjust rodent lifespan. This information will be integrated to develop a model featuring key processes which are altered globally and in an organ-specific manner as organisms change their lifespan. RELEVANCE (See instructions): Characterization of genes and processes that are associated with natural changes in lifespan may lead to the development of approaches that target the aging process and possibly delay it. Project 4 will carry out gene expression analyses to uncover these processes, focusing on DNA repair and forms occurring in long- lived rodents. This information will help develop strategies to delay the aging process in humans.